We previously examined expression of 329 human microRNAs and 13,000 protein-coding genes in primary human prostate tumors in collaboration with Carlo Croce at Ohio State University. This collaboration generated several of the earliest reports that showed altered microRNA expression in prostate cancer. Tumor microRNAs were both up- and down-regulated when compared with non-cancerous tissue. Notably, prostate tumors tended to express all members of the miR-106b-25 cluster at significantly higher levels than the non-cancerous prostate, which is consistent with miR-106b-25 having oncogenic properties in prostate cancer biology. In contrast, the expression of the miR-1-133 cluster was consistently lower in tumors than in the non-cancerous prostate, indicating that this microRNA cluster may act as a tumor suppressor. In two follow-up studies, we now showed that both up-regulation of miR-106b-25 expression and suppression of miR-1-133 expression are key steps in the progression of human prostate cancer. To further define the oncogenic role of the miR-106b-25 cluster in prostate cancer progression, we analyzed a large public dataset consisting of primary tumors, disease metastases, and disease recurrence status. Concordant with our previous findings, all miR-106-25-encoded microRNAs were significantly up-regulated in primary tumors. Expression of these microRNAs further increased in metastatic lesions, and specifically the expression of miR-106b was associated with early disease recurrence. To identify yet unknown oncogenic functions of miR-106b, we overexpressed this microRNA in human prostate cancer cells. The approach revealed that miR-106b suppressed the expression of pro-apoptotic caspase 7. Additional investigations made the novel observation that caspase 7 is a tumor suppressor and is associated with prostate cancer-specific survival. Most importantly, however, the combination of high miR-106b and low caspase-7 expression in primary tumors was found to be an independent predictor of early disease recurrence (adjusted hazard ratio=4.1; 95% confidence interval: 1.6-12.3). We also showed that phenotypes induced by miR-106b-25 expression in human prostate cancer cells, e.g., inhibition of apoptosis and altered adhesion properties, did not develop when caspase 7 expression was inhibited. Our data indicate a prominent role of miR-106b-25 in prostate cancer progression and disease outcome by altering survival- and cell adhesion-related pathways. We used a similar approach when we investigated the functions of the miR-1-133 cluster in prostate cancer biology. Here, we found that miR-1 expression is further reduced in distant metastasis, leading to early disease recurrence among patients with low miR-1 expression in their tumors. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings showed, for the first time, that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility. More recently, the Croce group reported that RNA expression from ultraconserved regions is altered in human cancer. Ultraconserved regions (UCR) are genomic segments of more than 200 base pairs that are absolutely conserved among mammalian species. This conservation suggests an important regulatory function that is encoded by these sequences. Thus, we hypothesized that UCR-encoded transcripts may have unidentified roles in the pathogenesis of human prostate cancer. Using microarrays representing 481 UCR-derived transcripts in sense and antisense direction, we discovered novel expression patterns for these transcripts that were associated with prostate cancer development, Gleason score, and extraprostatic extension. To search for possible functional interactions of ucRNAs as non-coding RNAs, RNA loop-loop interactions were computationally modeled to discover ucRNA:mRNA binding pairs. This approach yielded novel candidate interactions between ucRNAs and mRNAs. We also tested whether androgen exposure or epigenetic drug therapy may affect ucRNA transcript expression. These studies identified several ucRNAs that were responsive to treatment with either epigenetic drugs or a synthetic androgen, R1881. Lastly, we compared expression of selected ucRNAs with tumor mRNA and microRNA expression patterns and found global relationships between them. This first study of ucRNA expression in human prostate cancer indicates a dysregulated expression of these RNAs in the disease.